Molecular Biology of Norepinephrine Biosynthesis

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DESCRIPTION (provided by applicant): Norepinephrine (NE) is a crucial catecholamine neurotransmitter/hormone mediating a wide range of physiological responses. Alterations in NE neurotransmission are associated with several prevalent disorders, including cardiovascular disorders such as hypertension/hypotension, neuropsychiatric disorders, such as depression and in Parkinson's disease. Regulation of the expression of NE-biosynthetic enzymes, tyrosine hydroxylase (TH) and dopamine beta-hydroxylase (DBH), is a key mechanism of regulation of the NE systems. The specific aims of this proposal are: 1.) Determine the kinetics and the persistence of activation of TH and DBH transcription in rat locus coeruleus with different duration or repetitions of immobilization stress. 2.) Examine the dynamics of pathways involved in transcriptional activation of TH and DBH gene expression in locus coeruleus and adrenal medulla with different durations or repetitions of stress. 3.) Identify the induction of de novo synthesis of transient or long-lasting transcription factors in rat adrenal medulla and locus coeruleus associated with regulation of TH and DBH gene expression by exposure to single and repeated immobilization stress. 4.) Begin to characterize the mechanisms by which the above observed stress responsive factors cross-talk to regulate TH and DBH gene expression. Specifically examine the interaction of AP-l factors and Egr1 on the regulation of TH transcription. The results will provide a crucial understanding of the different transcriptional mechanisms of activation of gene expression of catecholamine producing systems in the CNS and the periphery with acute and repeated exposure to stressful situations. These findings will contribute to the development of new strategies to prevent the harmful maladaptive changes in catecholamine neurotransmission, while enhancing its beneficial adaptive aspects